Heterocyclic compounds useful as α2 -adrenoceptor antagonists

ABSTRACT

A compound of formula (I): ##STR1## or a pharmaceutically acceptable salt thereof, wherein: R 1  and R 2  may each represent hydrogen or alkyl providing that at least one of R 1  or R 2  represents alkyl; 
     R 3  and R 4  each represent hydrogen or R 3  and R 4  together represent a bond; 
     n represents an integer 1 or 2; 
     and m represents an integer 1 or 2; a composition containing such a compound and the method of using such compounds and compositions in medicine.

This application is a divisional application of application Ser. No.07/581,202, filed Sep. 10, 1990, now U.S. Pat. No. 5,021,445, which is acontinuation of application Ser. No. 260,004, filed Oct. 19, 1988, nowabandoned.

This invention relates to a certain class of heterocyclic compoundshaving activity as α₂ -adrenoceptor antagonists, to a process forpreparing such compounds, to pharmaceutical compositions containing suchcompounds and the use of such compounds and compositions in medicine.

European Patent Application, Publication No. 0238753 discloses certainheterocyclic compounds of the general formula (A): ##STR2## or apharmaceutically acceptable salt, ester or amide thereof, wherein: Zrepresents a residue of a substituted or unsubstituted aryl group,

X' represents O or NR^(o) wherein R^(o) represents a hydrogen atom, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaryl group, an alkanoyl group substituted or unsubstituted in the alkylmoiety, or an arylalkyl moiety substituted or unsubstituted in the arylmoiety,

n' represents an integer 1 or 2,

m' represents an integer 1 or 2,

p represents an integer 2 or 3, and

q represents an integer in the range of from 1 to 12.

The compounds of formula (A) are disclosed as having good α₂-adrenoceptor antagonist activity and to be of potential use for thetreatment and/or prophylaxis of hyperglycaemia and/or glaucoma and/orthe treatment of hypertension and/or depression and/or for inhibitingblood platelet aggregation.

A small class of heterocyclic compounds that fall within the generalformula (A) but which are not specifically disclosed in EP 0238753 hasnow surprisingly been discovered to have very good electivity for thepost-junctional α₂ -receptor and therefore shows good selectivity fromside effects. These compounds are therefore of particular value in thetreatment and/or prophylaxis of hyperglycaemia and/or the treatment ofhypertension and/or for inhibiting blood platelet aggregation.

Accordingly, the present invention provides a compound of formula (I):##STR3## or a pharmaceutically acceptable salt thereof, wherein: R¹ andR² may each represent hydrogen or alkyl providing that at least one ofR¹ and R² represents alkyl;

R³ and R⁴ each represent hydrogen or R³ and R⁴ together represent abond;

n represents an integer 1 or 2;

and m represents an integer 1 or 2.

Suitably, R¹ and R² each represent alkyl.

Preferably, R¹ and R² each represent methyl.

Suitably, R³ and R⁴ each represent hydrogen.

Suitably, R³ and R⁴ together represent a bond.

Suitably n represents 1.

Suitably m represents 1.

In a preferred aspect the present invention provides a compound selectedfrom the group consisting of:

2(2H-[7-chloro-4-(3-methylbut-2-enyloxy)-1,3-dihydroisoindole]methyl)-4,5-dihydromidazole;and

2-(2H-[7-chloro-4-(3-methylbutyloxy)-1,3-dihydroisoindole]methyl)-4,5-dihydromidazole;or a pharmaceutically acceptable salt thereof.

Suitable pharmaceutically acceptable salts of the compound of formula(I) include acid addition salts.

Suitable pharmaceutically acceptable acid addition salt of compound (I)include pharmaceutically acceptable inorganic salts such as thesulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide andpharmaceutically acceptable organic acid addition salts such as acetate,tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate, c-ketoglutarate, α-glycerophosphate, andglucose-1-phosphate. Preferably the acid addition salt is ahemisuccinate, hydrochloride, α-ketoglutarate, α-glycerophosphate orglucose-1-phosphate, in particular the hydrochloride salt.

When used herein the term `alkyl` includes straight and branched chainalkyl groups containing from 1 to 12 carbon atoms, suitably 1 to 6carbon atoms, such as methyl, ethyl, propyl and butyl groups.

The present invention also provides a process for the preparation of acompound of formula (I), or a pharmaceutically acceptable salt thereof,which process comprises cyclising a compound of formula (II): ##STR4##wherein R¹, R², R³, R⁴, m and n are as defined in relation to formula(I); and thereafter, if required, converting a compound of formula (I)into a further compound of formula (I) and/or forming a pharmaceuticallyacceptable salt thereof. A compound of formula (II) may be prepared byreacting a compound of formula (III): ##STR5## wherein R¹, R², R³, R⁴, mand n are as defined in relation to formula (I) and A represents --CN or--CO₂ R wherein R represents C₁₋₆ alkyl, with 1,2-diaminoethane or anactivated form thereof.

A suitable activated form of 1,2-diaminoethane is the trimethylaluminiumadduct of 1,2-diaminoethane. The activated form of 1,2-diaminoethane isgenerally the preferred reagent when A represents --CO₂ R.

Suitably, R represents methyl.

A compound of formula (III) may be prepared by reacting a compound offormula (IV): ##STR6## wherein m and n are as defined in relation toformula (I) and A is as defined in relation to formula (III), with acompound of formula (V): ##STR7## wherein R¹, R², R³ and R⁴ are asdefined in relation to formula (I) and X represents a leaving group,preferably a bromine atom.

The compounds of formula (V) are known compounds or they may be preparedusing methods analogous to those used to prepare known compounds.

A compound of formula (IV) may be prepared by reacting a compound offormula (VI): ##STR8## wherein m and n are as defined in relation toformula (I) and A is as defined in relation to formula (III) and R^(y)represents a hydroxyl protecting group, with a chlorinating agent, andthereafter removing the protecting group R^(y).

A suitable chlorinating agent is any agent capable of inserting achlorine atom in the required position on the phenyl group of thecompound of formula (VI) without affecting the rest of the molecule.

Conveniently, sulphuryl chloride may be used as the chlorinating agent.

A compound of formula (VI) may be prepared by reacting a compound offormula (VII): ##STR9## wherein m, n and Ry are as defined in relationto formula (VI) and X¹ represents a leaving group, with a compound offormula (VIII):

    H.sub.2 N--CH.sub.2 --A                                    (VIII)

wherein A is as defined in relation to formula (III), and thereafter, ifrequired, converting a compound of formula (VI) into another compound offormula (VI).

Suitably, X¹ represents a halogen atom, especially a chlorine or bromineatom, a methanesulphonate group or a p-toluenesulphonate group.

Preferably X¹ represents a bromine atom.

Suitable conversions of one compound of formula (VI) into anothercompound of formula (VI) include those wherein A, in formula (VI), isconverted from one value into another value: for example a compound offormula (VI) wherein A represents nitrile may be converted into acompound of formula (VI) wherein A represents --CO₂ R, wherein R is asdefined in relation to formula (III), by any conventional procedure, forexample by hydrolysis to give the corresponding carboxylic acid followedby esterification.

Suitable conditions for hydrolysing, the nitrile group include acidconditions, for example using aqueous hydrobromic acid.

Suitable conditions for esterification are well known in the art andinclude treatment with the appropriate alcohol under acidic conditions.

A compound of formula (VII) may be prepared by reaction of a compound offormula (IX): ##STR10## wherein m, n and R^(y) are as defined inrelation to formula (VI), with a reagent capable of converting a moiety--CH₂ --OH into a moiety --CH₂ --X¹.

When X¹ represents a halogen atom, especially a chlorine or bromineatom, a suitable reagent is a halogenating agent such as a phosphoroustrihalide.

When X¹ is chlorine a preferred reagent is phosphorous trichloride.

When X¹ is bromine a preferred reagent is phosphorous tribromide.

When X¹ represent a methanesulphonate group, a suitable reagent is amethanesulphonyl halide especially methanesulphonyl chloride.

When X¹ represents a p-toluenesulphonate group, a suitable reagent is ap-toluenesulphonyl halide especially p-toluenesulphonyl chloride.

A compound of formula (IX) may be prepared by reducing a compound offormula (X): ##STR11## wherein R^(y) is as defined in relation toformula (VI), r and s each represent either zero or 1 and R⁵ is a C₁₋₆alkyl group.

A suitable reducing agent is a complex metal hydride such as lithiumaluminium hydride.

A compound of formula (X) may be prepared from a compound of formula(XI): ##STR12## wherein R⁵, r and s are as defined in relation toformula (X), by converting the hydroxy group therein into a protectedhydroxyl group --OR^(y).

Suitably, R⁵ is a methyl group.

Suitably, r and s both represent zero.

The compounds of formula (XI) are known compounds or they may beprepared using methods analogous to those used to prepare knowncompounds, for example those disclosed in Helv. Chim. Acta (1931), 14,511.

Suitable conversions of one compound of formula (I) into anothercompound of formula (I) include those in which a compound wherein R³ andR⁴ together represent a bond is coverted into a compound wherein R³ andR⁴ each represent hydrogen; such a convension may be carried out usingany conventional procedure such as catalytic reduction.

The salts of the compounds of formula (I) may be prepared by theappropriate conventional procedure.

The cyclisation of compounds of formula (II) may be carried out underany appropriate conditions, using any suitable solvent system andtemperature range appropriate to the particular compound of formula(II), but usually at an elevated temperature.

Favourably, for the preparation of a compound of formula (I), thecompound of formula (II) is not isolated from the reaction between theappropriate compound of formula (III) and 1,2-diaminoethane or anactivated form thereof, thus the compound of formula (II) is convertedin-situ to a compound of formula (I).

Thus, in this favoured form of the process for the preparation ofcompounds of formula (I), the appropriate compound of formula (III) and1,2-diaminoethane are reacted together at an elevated temperature, forexample within the range 80° C. to 130° C., preferably 110° C., in anysuitable solvent such as toluene; favourably for reactions involving1,2-diaminoethane the reaction is carried out using 1,2-diaminoethane assolvent; preferably the reaction is carried out in the presence of acatalytic amount of carbon disulphide; preferably the reaction iscarried out under an atmosphere of nitrogen.

It will be understood that under the abovementioned conditions thecompound of formula (II) initially formed in the reaction between thecompound of formula (III) and 1,2-diaminoethane or an activated formthereof; subsequently undergoes cyclisation to give the requiredcompound of formula (I).

Accordingly, in an alternative aspect the present invention provides aprocess for the preparation of a compound of formula (I) which processcomprises reacting a compound of formula (III) with 1,2-diaminoethaneand thereafter if required converting a compound of formula (I) into apharmaceutically acceptable salt thereof.

The reaction between compounds of formulae (IV) and (V) may be carriedout in any suitable solvent such as a lower alkyl ketone, for examplebutanone, at any convenient temperature, suitably at the refluxtemperature of the solvent, in the presence of a base, preferablypotassium carbonate.

The reaction between the compounds of formula (VI) and the chlorinatingagent may be carried out under conditions appropriate to the nature ofthe chlorinating agent. Thus, for example when the chlorinating agent issulphuryl chloride, the reaction may conveniently be carried out in anysuitable solvent, such as dichloromethane or acetic acid, at a low toambient temperature, conveniently at ambient temperature.

A compound of formula (VII) may be prepared from a compound of formula(IX) by using conditions appropriate to the nature of the reagentcapable of converting a moiety --CH₂ --OH into a moiety --CH₂ --X¹, forexample:

(i) when X¹ represents halogen, especially a chlorine or bromine atomand the reagent is a phosphorus trihalide, the reaction may convenientlybe carried out at low to ambient temperature, for example at 5° C., inany suitable solvent, such as diethyl ether;

(ii) when X¹ represents a methanesulphonate group or ap-toluenesulphonate and the reagent is a methanesulphonyl halide or atoluenesulphonyl halide respectively, the reaction may be carried out inany suitable solvent, such as pyridine, at a low to ambient temperature,suitably at ambient temperature.

The reaction between the compounds of formulae (VII) v and (VIII) mayconveniently be carried out in an aprotic solvent, such asdimethylformamide, preferably at a slightly elevated temperature, forexample at a temperature in the range of between 20° C. and 60° C.

The reduction of the compound of formula (X) is carried out underconditions appropriate to the reducing agent used. Thus, when lithiumaluminium hydride is the reducing agent, the reaction may convenientlybe carried out in an aprotic solvent, such as diethyl ether, at low toelevated temperature, more usually at the reflux temperature of thesolvent.

In the abovementioned processes any reactive groups may be present asprotecting groups. Suitable protecting groups are those usedconventionally in the art; for example a suitable hydroxyl protectinggroup R^(y) is a benzyl group.

The conditions of preparation and removal of the relevant protectinggroup are those used conveniently in the art. Thus, when R^(y) is abenzyl group, the compound of formula (XI) may conveniently be reactedwith benzyl bromide in the presence of a base such as potassiumcarbonate, in a solvent such as dimethylformamide, conveniently at anelevated temperature, for example 80° C. Also, when Ry is a benzyl groupthe benzyl group may be removed by using a reagent such as borontrifluoride dimethylsulphide complex.

The present invention also provides a compound of formula (I), or apharmaceutically acceptable salt thereof, for use as an activetherapeutic substance.

In a particular aspect, the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment and/or prophylaxis of hyperglycaemia.

In a further aspect the present invention provides a compound of formula(I), or a pharmaceutically acceptable salt thereof, for inhibiting bloodplatelet aggregation.

In a further aspect, the present invention provides a compound of thegeneral formula (I), or a pharmaceutically acceptable salt thereof, foruse in the treatment of hypertension in human or non-human mammals.

A compound of the general formula (I), or a pharmaceutically acceptablesalt thereof, may be administered per se or, preferably, as apharmaceutical composition also comprising a pharmaceutically acceptablecarrier.

Accordingly, the present invention also provides a pharmaceuticalcomposition comprising a compound of the general formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier therefor.

As used herein the term "pharmaceutically acceptable" embracescompounds, compositions and ingredients for both human and veterinaryuse: for example the term "pharmaceutically acceptable salt" embraces aveterinarily acceptable salt.

The composition may, if desired, be in the form of a pack accompanied bywritten or printed instructions for use.

Usually the pharmaceutical compositions of the present invention will beadapted for oral administration, although compositions foradministration by other routes, such as by injection and percutaneousabsorption, are also envisaged.

Particularly suitable compositions for oral administration are unitdosage forms such as tablets and capsules. Other fixed unit dosageforms, such as powders presented in sachets, may also be used.

In accordance with conventional pharmaceutical practice the carrier maycomprise a diluent, filler, disintegrant, wetting agent, lubricant,colourant, flavourant or other conventional adjuvant.

Typical carriers include, for example, microcrystalline cellulose,starch, sodium starch glycollate, such as Harry's Cosmeticologypublished by Leonard Hill Books, Remington's Pharmaceutical Sciences,and the British and US Pharmacopoeias.

The compositions of the present invention may be prepared using anyconventional process, for example those disclosed in the abovementionedreference texts.

Most suitably the composition will be formulated i unit dose form. Suchunit dose will normally contain an amount of the active ingredient inthe range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and moreespecially 0.1 to 250 mg.

The present invention further provides a method for the treatment and/orprophylaxis of hyperglycaemia in a human or non-human mammal whichcomprises administering an effective, non-toxic, amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof, to ahyperglycaemic human or non-human mammal in need thereof.

The present invention further provides a method for the treatment ofhypertension in a human or non-human mammal, which comprisesadministering an effective, non-toxic, amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof, to an hypertensivehuman or non-human mammal.

The invention also provides a method for inhibiting blood plateletaggregation in a human or non-human mammal, which method comprisesadministering an effective non-toxic amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof, to a human ornon-human mammal in need thereof.

Conveniently, the active ingredient may be administered as apharmaceutical composition hereinbefore defined, and this forms aparticular aspect of the present invention.

In the treatment and/or prophylaxis of hyperglycaemic humans or thetreatment of hypertensive humans the compound of the formula (I), or apharmaceutically acceptable salt thereof, may be taken in doses, such asthose described above, one to six times a day in a manner such that thetotal daily dose for a 70 kg adult will generally be in the range offrom 0.1 to 6000 mg, and more usually about 1 to 1500 mg.

In the treatment and/or prophylaxis of hyperglycaemic non-human mammals,especially dogs, the active ingredient may be adminstered by mouth,usually once or twice a day and in an amount in the range of from about0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg.

In the inhibition of platelet aggregation in human or non-human mammals,dosage regimes are as indicated above for the treatment and/orprophylaxis of hyperglycaemic human or non-human mammals.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment and/or prophylaxis of hyperglycaemia.

The present invention further provides the use of a compound of formula(I) or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the inhibition of blood platelet aggregation and/orthe treatment of hypertension.

No toxicological effects are indicated when a compound of formula (I),or a pharmaceutically acceptable salt thereof, is administered in any ofthe abovementioned dosage ranges.

The following Examples illustrate the invention but do not limit it inany way.

EXAMPLE 12-(2H-[7-Chloro-4-(3-methylbut-2-enyloxy)-1,3-dihydroisoindole]methyl)-4,5-dihydroimidazole##STR13##

A mixture of 1.0 g (3.6 mmol) of2H-[7-Chloro-4-(3-methylbut-2-enyloxy)-l,3-dihydroisoindole]acetonitrile,1 ml (14.9 mmol) of 1,2-diaminoethane and 5 drops of carbon disulphidewas heated at 110° C. under an atmosphere of nitrogen. After 6 hours themixture was cooled and partitioned between dichloromethane and water.The or9anic layer was separated, dried and evaporated to yield the crudeproduct.

Recrystallisation from ethyl acetate gave the title compound as an offwhite solid.

1H-nmr δ (CDCl₃):

7.10 (1H,d); 6.66 (1H,d); 5.42 (1H,t); 4.49 (2H,d); 4.03 (4H,s); 3.7-3.5(1H,broad signal, exchanges with D₂ O); 3.65 (4H,s); 3.55 (2H,s); 1.78(3H,s); 1.72 (3H,s).

EXAMPLE 22-(2H-[7-Chloro-4-(3-methylbutyloxy)-1,3-dihydroisoindole]methyl)-45-dihydroimidazole ##STR14##

The title compound, mp. 128°-129°, was obtained from 1.0 g (3.59 mmole)of 2H-[7-chloro-4-(3-methylbutyloxy)-1,3-dihydroisoindole)acetonitrileand 1 ml (14.9 mmole) of 1,2-diaminoethane by an analogous procedure tothat described in Example 1.

¹ H-nmr δ (CDCl₃ +D₂ O):

7.12 (1H, d); 6.66 (1H, d); 4.02 (4H, s); 3.98 (1H, d); 3.96 (1H, d);3.65 (4H, s); 3.59 (2H, s); 1.9-1.7 (1H, m); 1.66 (1H, d); 1.63 (1H, d);0.95 (6H, d).

Procedure 1 Dimethyl 3-benzyloxyphthalate ##STR15##

A mixture of 14.5 g (69 mmol) of dimethyl 3-hydroxyphthalate, 9.6 g (69mmol) of anhydrous potassium carbonate and 8.23 ml (69 mmol) of benzylbromide in 50 ml of dry dimethylformamide was heated with stirring at80° C.

After 18 hours the mixture was cooled and poured into 500 ml of water,and extracted into diethyl ether 3×100 ml). The combined organicextracts were dried and evaporated to yield the crude compound as anoil. Chromatography over silica gel eluting with hexane/diethyl ether(0→50%) gave the title compound as an oil.

1H-nmr δ (CDCl₃):

7.7-7.0 (8H,m); 5.14 (2H,s); 3.90 (3H,s); 3.78 (3H,s).

Procedure 2 3-Benzyloxy-1,2-bishydroxymethylbenzene ##STR16##

To a suspension Of 10 g Of lithium aluminium hydride in 300 ml of drydiethyl ether was added dropwise a solution of 18 g (60 mmol) ofdimethyl 3-benzyloxy phthalate in 125 ml of dry diethyl ether.

After heating under reflux for 4 hours the mixture was cooled andtreated sequentially with 10 ml of water, 10 ml of 10% sodium hydroxidesolution and 20 ml of water. The resultant mixture was filtered and thefiltrate evaporated to yield the title compound as a pale yellow oil.

¹ H-nmr δ (CDCl₃):

7.6-7.1 (6H,m); 7.0-6.8 (2H,m); 5.04 (2H,s); 4.76 (2H,s); 4.55 (2H,s);3.8-3.3 (2H,broad signal, exchanges with D₂ O).

Procedure 3 3-Benzyloxy-1,2-bisbromomethylbenzene ##STR17##

To a solution of 12 g (49.2 mmol) of3-benzyloxy-1,2-bishydroxymethylbenzene in 350 ml of dry diethyl etherat 5° C. was added dropwise 30 ml (252 mmol) of phosphorus tribromide in50 ml of dry diethyl ether. After stirring at room temperature for 14hours the mixture was poured onto 500 g of ice, the organic layer wasseparated, washed with 200 ml of water, 200 ml of saturated sodiumbicarbonate solution and 200 ml of brine. Drying and evaporation of theresultant organic phase gave the title compound as a white solid.

¹ H-nmr δ (CDCl₃):

7.7-7.1 (6H,m); 7.1-6.9 (2H,m); 5.17 (2H,s); 4.86 (2H,s); 4.65 (2H,s).

Procedure 4 2H-(4-Benzyloxy-1,3-dihydroisoindole)acetonitrile ##STR18##

To a mixture of 5.14 g (55.5 mmol) of aminoacetonitrile hydrochlorideand 18.3 ml (134 mmol) of triethylamine in 75 ml of drydimethylformamide at 50° C. was added dropwise a solution of 15 g (40.5mmol) of 3-benzyloxy-1,2- bisbromomethylbenzene in 50 ml of drydimethylformamide. The temperature was maintained at 50° C. for 3 hours.After stirring at room temperature for 14 hours the mixture was pouredinto 500 ml of water. The resultant aqueous phase was extracted threetimes with 150 ml portions of diethyl ether. The combined organic layerswere dried and evaporated to yield a pale yellow oil.

¹ H-nmr (CDCl₃):

7.5-6.6 (8H,m); 5.00 (2H,s); 4.03 (4H,s); 3.68 (2H,s)

Procedure 5 2H-(4-Benzyloxy-7-chloro-1,3-dihydroisoindole) acetonitrile##STR19##

To a solution of 6.9 g (26.1 mmol) of2H-(3-benzloxy-1,3-dihydroisoindole)acetonitrile in 70 ml ofdichloromethane at room temperature was added 2.1 ml (26.1 mmol) ofsulphuryl chloride. After stirring for 0.5 hours a further 2.1 ml ofsulphuryl chloride was added. The mixture was stirred for 1 hour afterwhich the solvent was evaporated. The resultant mixture was partitionedbetween saturated sodium bicarbonate solution and dichloromethane. Theorganic phase was separated, dried and evaporated to yield the crudeproduct. Chromatography over silica gel, eluting with dichloromethane,gave the title compound as a pale yellow oil.

¹ H-nmr δ (CDCl₃ ):

7.5-7.1 (5H,m); 7.01 (1H,d); 6.50 (1H,d); 4.88 (2H,s) 4.02 (4H,s); 3.65(2H,s).

Procedure 6 2H-(7-Chloro-4-hydroxy-1.3-dihydroisoindole)acetonitrile##STR20##

To a solution of 3.2 g (10.7 mmol) of2H-(4-benzloxy-7-chloro-1,3-dihydroisoindole)acetonitrile in 40 ml ofdichloromethane at room temperature, under an atmosphere of nitrogen,was added 15.6 ml (120 mmol) of boron trifluoride dimethylsulphidecomplex. After stirring for 3 hours the mixture was poured into water.The resultant aqueous phase was neutralised with solid sodiumbicarbonate and extracted (4 x 100 ml aliquots) with dichloromethane.The combined organic extracts were dried and evaporated to yield thecrude product. Chromatography over silica gel, eluting withdichloromethane/methanol (0→2%), gave the title compound.

¹ H-nmr δ (CDCl₃):

6.95 (1H,d); 6.60 (1H,s exchanges with D₂ O); 6.48 (1H,d); 4.05 (4H,s);3.73 (2H,s).

Procedure 72H-[7-Chloro-4-(3-methylbut-2-enyloxy)-1,3-dihydroisoindole]acetonitrile##STR21##

A mixture of 0.8 g (3.8 mmol) of2H-(7-chloro-4-hydroxy-1,3-dihydroisoindole)acetonitrile and 1.0 g (7.2mmol) of anhydrous potassium carbonate in 20 ml of butanone was heatedunder reflux with stirring for 1 hour. The mixture was cooled to roomtemperature and 0.62 g (3.8 mmol) of 90% 1-bromo-3-methylbut-2-ene wasadded. Heating was recommenced and continued for 16 hours after whichtime the mixture was cooled and evaporated to dryness. The residue waspartitioned between dichloromethane and water, the organic layer wasseparated and dried to yield the title compound as an oil.

¹ H-nmr δ (CDCl₃):

7.10 (1H,d); 6.67 (1H,d); 5.42 (1H,t); 4.50 (2H,d); 4.03 (4H,s); 3.68(2H,s); 1.80 (3H,s); 1.76 (3H,s).

Procedure 82H-[7-Chloro-4-(3-methylbutyloxy)-1,3-dihydroisoindole]acetonitrile.##STR22##

2H-(7-Chloro-4-hydroxy-1,3-dihydroisoindole) acetonitrile, 2.12 g (8.65mmol) in 25 ml of dry dimethylformamide (DMF) was added to a suspensionof 0.69 g (17.25 mmole) of 60% sodium hydride in 10 ml of DMF. Afterstirring at room temperature for 0.25 h and cooling to 5° C., 1-bromo-3-methylbutane, 1 ml (8.35 mmol), in 5 ml of DMF was added. The reactionmixture was stirred overnight at room temperature, poured into 100 ml ofwater and then extracted twice, each time with 100 ml portions ofdiethyl ether. The organic layer was dried and evaporated to yield thetitle compound as a light brown oil.

¹ H-nmr δ (CDCl₃):

7.12 (1H, d); 6.66 (1H, d); 4.11 (4H, s); 4.0-3.9 (2H, m); 3.75 (2H, s);2.0-1.5 (3H, m); 0.94 (6H, d).

Pharmacological Data

Demonstration of the Pharmacological Selectivity for Pre- andPost-junctional α₂ -Adrenoceptors.

To determine post-junctional α₂ -adrenoceptor activity, ring segments ofrabbit lateral saphenous vein were mounted in organ baths at 37° C.containing Krebs medium. Contractions of this tissue in response tonoradrenaline are mediated via post-junctional α₂ -adrenoceptors(Alabaster et al, 1985) and therefore the ability of α₂ -adrenoceptorantagonists to pharmacologically antagonise such contractions gives aquantitive measure of the activity of compounds for this receptorsubtype.

Pre-junctional activity is estimated by the ability of α₂ -adrenoceptorantagonists to reverse a clonidine-induced inhibition of [³H]-noradrenaline release from segments of rabbit aorta. Rings of rabbitabdominal aorta were incubated at 37° C. in Krebs medium containing 40μCi of [³ H]-noradrenaline (specific activity 10-30Ci/mmol) for 1 hour.Tissues were then mounted vertically between parallel platinumelectrodes and superfused with tritium-free Krebs medium. Electricalstimulation was carried out using square wave pulses of 0.5 msecduration and 100 V were delivered to the tissues at a frequency of 2 Hz.The superfusate was collected in 3 minute fractions. Six stimuli (S₁-S₆) were applied to each tissue. Clonidine was added to the superfusionstream after S₂ at a concentration of 0.01 μM and again after S₃ at aconcentration of 0.1 μM. Each antagonist added after S₄ and a furtherconcentration of clonidine (1 μM) infused after S₅. At the end of eachexperiment each aortic segment solubilised in 150 μl of Fisosolve^(R)tissue solubiliser and the radioactivity of both superfusate samples andaortic rings determined by liquid scintillation spectroscopy.

Results are calculated by the method of Docherty et al. 1982, withstimulation evoked overflow of tritium

expressed as a percentage of the tritium content of the tissue at theonset of the respective stimulation period.

    ______________________________________                                        Example      Post-synaptic                                                                            Pre-synaptic                                          Number       PA.sub.2   PA.sub.2                                              ______________________________________                                        1            6.6        <5.0                                                  2            6.7        5.4                                                   ______________________________________                                    

Alabaster V. A., Keir R. F. and Peters C. J. (1985)Naunun-Schmiedeberg's Arch Pharmacol 330, 33-36. Docherty J. R., GothertM., Dieckhoffer C. and Starke K. (1982) Arzneim-Forsch, Drug Res., 32,1534-1540.

We claim:
 1. A compound of formula (I): ##STR23## or a pharmaceuticallyacceptable salt thereof, wherein: R¹ and R² may each represent hydrogenor C₁₋₁₂ alkyl providing that at least one of R¹ and R² representsalkyl;R³ and R⁴ each represent hydrogen; and m and n are equal to eachother and represent an integer 1 or
 2. 2. A compound according to claim1, wherein R¹ and R² each represent alkyl.
 3. A compound according toclaim 1, wherein R¹ and R² each represent methyl.
 4. A compoundaccording to claim 1, wherein n represents
 1. 5. A compound according toclaim 1, wherein m represents
 1. 6. A compound according to claim 1which is2-(2H-[7-chloro-4-(3-methylbutyloxy)-1,3-dihydroisoindole]methyl)-4,5-dihydroimidazoleor a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition for use as an alpha-2-adrenoreceptor antagonist whichcomprises a pharmaceutically effective amount of a compound of formula(I) as defined by claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier therefor.
 8. A methodfor the treatment of hyperglycaemia in a human or non-human mammal whichcomprises administering an effective, non-toxic, amount of a compound offormula (I) as recited in claim 1, or a pharmaceutically acceptable saltthereof, to a hyperglycaemic human or non-human mammal in need thereof.9. A method for the treatment and/or prophylaxis of hypertension and/orinhibiting blood platelet aggregation in a human or non-human mammal,which method comprises administering an effective non-toxic amount of acompound of formula (I) as recited in claim 1, or a pharmaceuticallyacceptable salt thereof, to a human or non-human mammal in need thereof.